Age-related changes in synapse ultrastructure and neuroprotective effect of dietary curcumin in the lateral...

Elucidating the impact of aging on the structure and function of neurons is key to understanding the mechanisms underlying synaptic dysfunction and ensuing susceptibility to age-related cognitive decline. The role of structural alterations in the lateral prefrontal cortex (LPFC) has been extensively addressed. In addition, numerous studies point to the importance of inflammation and the increase of oxidative stress during aging, with mitochondria as one of the key cellular organelles involved. Here, we used 3D high-resolution serial block-face scanning electron microscopy to visualize the ultrastructure of synapses on pyramidal neurons in area 46 of the LPFC in rhesus monkeys at different stages across their adult lifespan. Our results revealed a general loss of synapses with age, mainly driven by the loss of asymmetric axospinous synapses. We observed a larger bouton volume but not larger spine or postsynaptic density (PSD) surface in the aged group compared to all other groups, along with a weaker correlation between spine and synaptic size. Additionally, we found morphological changes in mitochondria in the aged compared to middle-aged and young monkeys. Altogether, our data show ultrastructural changes that suggest an improper synaptic scaling and possible mitochondrial dysfunction that might take place after middle-age. We studied the impact of curcumin as a long-term dietary supplement and found that it ameliorated some of these age-related changes at middle-age by preserving the spine and PSD morphology and their size relationship, and also mitochondrial morphology, which might allow for maintaining synaptic function during aging, resulting in a delayed cognitive decline.